We have designed and synthesized novel HDAC/PI3K dual inhibitors, identifying several novel molecules that inhibit both targets with single-digit nanomolar potency. Selected compounds have been tested in the NCI60 cell line panel, showing anti-proliferation and cell-killing activity in several cell lines. A subset of these were examined in cell-based target engagement assays, confirming that the dual inhibitors engage both PI3K-delta and HDAC6 in cells. Our first cancer target will be FLT3-resistant acute myeloid leukemia (AML), based upon the potent cytotoxic activity of the compound, TRND00507679. We have completed development of the nano-particle formulation for TRND00507679 and are scaling-up synthesis. Formulation development of a second promising compound, TRND00421925, is ongoing. Work to date has resulted in submission of an international patent application.